The present invention relates to inducing symptoms in non-human mammals similar to those in AIDS-infected individuals, particularly symptoms of neurological deficit, thereby creating an effective animal model for AIDS.
The development of effective anti-AIDS therapies depends to a large extent on the development and utilization of animal models for AIDS. The use of monkeys as a model for AIDS studies are of limited use. Given the prohibitive cost, only a limited number of monkeys are used per study. Furthermore, testing macaques infected with SIV, the causative agent of simian AIDS, may not be satisfactory because the same neurological deficits observed in human AIDS patients, e.g., dementia, are not observed. A transgenic mouse strain is currently available. The use of transgenic animals, however, is cost prohibitive.
Developing model in vivo systems generally involves the administration of the etiologic agent of AIDS, the HIV virus. Researchers and laboratory personnel may be wary of handling the infectious live virus to the detriment of furthering research in this area.
As such, potential anti-AIDS drugs are often sent directly to clinical trials without having been tested for side effects or efficacy in an animal model. Many more drugs than necessary are therefore likely to enter clinical trials without specifically targeting agents shown to be promising in animal models. Human clinical studies themselves are problematic in that in many instances they require patients to be free of the effects of the drug zidovudine (AZT), which can temporarily improve neurological symptoms seen with AIDS.
A model is thus needed which alleviates the above problems where data is generated in a timely fashion in order to permit potential anti-AIDS drugs to readily enter clinical trials.
Viruses may use endogenous peptide receptors to infect cells. The HIV virus has been shown to bind to a surface molecule known as the CD4 or T4 region, which is present on various cells susceptible to HIV infection, including T lymphocytes and macrophages.
Patients with AIDS exhibit not only symptoms arising from immunodeficiency, but also neuropsychological deficits. The central nervous and immune systems share a large number of specific cell-surface recognition molecules, serving as receptors for neuropeptide-mediated intercellular communication. The neuropeptides and their receptors show profound evolutionary stability, being highly conserved in largely unaltered form in unicellular as well as higher animals. Furthermore, the central nervous and immune systems show common CD4 (T4) cell-surface recognition molecules which serve as receptors for the binding of HIV envelope glycoprotein (gp 120). The gp120 glycoprotein has been shown to affix non-covalently to the brain membranes of humans, rats and monkeys and to cells of the immune system.
The envelope glycoprotein of the HIV virus, gp 120, has been associated with antigenicity, infectivity and neurotoxicity. HIV-induced neurotoxicity appears to be associated with gp 120-CD4 binding resulting in increased intracellular free calcium. Calcium channel blockers such as nimodipine have been shown to antagonize this effect. In vitro neurotoxicity of gp 120 has been described, for example, by Brenneman et al. Nature 335 (1988) 639-642; Brenneman et al. Drug Dev. Res. 15 (1988) 361-369; Dryer et al. Science 248 (1990) 364-367; and Dawson et al. Soc. Neurosci 18 (abstr)(1992) 321.1. Neurological deficits have been observed in neonatal rats following systemic administration of gp-120. Hill et al. Brain Res. 603(2) (1993) 222-223. Gp120 neurotoxicity of rat cortical neurons with apoptosis has also been described. Muller et al. Eur. J. Pharm. 226 (1992) 209-214. Direct injection of gp-120 to the cerebral ventricles was reported to result in memory impairments in adult rats. Glowa et al. Brain Res. 570 (1992) 49-53.
Peptide T is a modified octapeptide homologous to a subunit sequence of the endogenous Vasoactive Intestinal Peptide (VIP) described by Pert, et al. Proc. Natl. Acad. Sci. 83 (1986) 9254-9258 that was found to exist in homologous form in the 120 Kilodalton envelope glycoprotein (gp120) of all HIV isolates sequenced. Autoradiographic mapping with labelled gp120 has shown greater binding in VIP receptor rich areas. In vitro studies have demonstrated that VIP and peptide T inhibit both the binding of gp120 to brain tissue and HIV replication in cell culture. Intravenous peptide T in doses up to 224 mg/day has shown no toxicity and has resulted in improved neurocognitive functioning in the HIV-infected patients. Brenneman, D. et al. Nature 335 (1988) 639-642; Bridge, T P et al., Lancet 2 (1989) 226-227; Hill, J. M. et al. (abstr.) Sixth Intl. Conf. on AIDS vol. 1, page 330.
Peptide T has been reported to block gp120 binding to inhibit infectivity of patient primary viral isolates. VIP or peptide T potently inhibit the neurotoxic effects of gp120 on cells and in animals. While cortical neuronal loss and behavioral deficits have been reported in neonatal rats receiving gp120, Hill, J. M., et al. Brain Res. 603(2) (1993) 222-223, all of these abnormalities were reversed by co-administered peptide T.
The present invention provides a model for AIDS in non-human animals whereby symptoms similar to those in AIDS-infected individuals are induced, particularly symptoms of neurological deficit. Peptide T, VIP, gp120 or a derivative or peptide analog thereof is administered intrathecally to a non-human mammal in concentrations effective to induce these symptoms.
It is an object of the present invention to provide a model for AIDS in non-human mammals.
It is a further object of the present invention to provide a method of inducing symptoms similar to those in AIDS-infected individuals in non-human mammals, particularly rats.
It is an object of the present invention to provide a method of inducing neurological deficit in non-human mammals, particularly rats.
Moreover, it is an object of the present invention to induce the desired symptoms without the necessity of handling the live, infectious AIDS virus.
Finally, it is an object of the present invention to provide a reliable, cost-effective, relatively simple and time-efficient model for testing the effect of potential anti-AIDS drugs.
The above and other objectives, features and advantages of the present invention will become apparent to those skilled in the art from the following descriptions and are within the scope of the present invention.